Translating the Force - mechano-sensing GPCRs

Incorporating mechanical cues into cellular responses allows us to experience our direct environment. Specialized cells can perceive and discriminate between different physical properties such as level of vibration, temperature, or pressure. Mechanical forces are abundant signals that also shape general cellular responses such as cytoskeletal rearrangement, differentiation, or migration and contribute to tissue development and function. The molecular structures that perceive and transduce mechanical forces are specialized cytoskeletal proteins, cell junction molecules, and membrane proteins such as ion channels and metabotropic receptors. G protein-coupled receptors (GPCRs) have attracted attention as metabotropic force receptors as they are among the most important drug targets. This review summarizes the function of mechano-sensitive GPCRs, specifically, the angiotensin II type 1 receptor and adrenergic, apelin, histamine, parathyroid hormone 1, and orphan receptors, focusing particularly on the advanced knowledge gained from adhesion-type GPCRs. We distinguish between shear stress and cell swelling/stretch as the two major types of mechano-activation of these receptors and contemplate the potential contribution of the force-from-lipid and force-from-tether models that have previously been suggested for ion channels.